Pancreatic ductal adenocarcinomas (PDAC) continue to have the worst prognosis of all solid tumors with a five-year survival of less than 5%. The high mortality rate from PDAC is mainly caused by widepread invasive and metastatic disease at the time of diagnosis and general resistance to chemotherapy. Biologically targeted therapies are under investigation with the hope of improving survival of patients with PDAC. To date these therapies provide very modest increase in survival length with no increase in overall survival. Currently gaps exist between known genetic alterations that give rise to PDAC with how these alterations impact critical signaling pathways and networks that mediate invasiveness and chemoresistance. Our preliminary data details the discovery of a dynamic cross talk between Ron kinase and Smad-independent TGF2 signaling that promotes tumor growth, invasion and metastasis. Moreover, we demonstrate that Ron is not aberrantly expressed in the cancer stem cell population but is induced during tumor progression as a result of loss or attenuation of Smad signaling and through transcriptional activation in part through HIF-11. Based on these findings we hypothesize that the TGF2/RON axis plays an important role in progression of PDAC and that understanding the interactions of these pathways will lead to novel strategies for improving therapy. To test this hypothesis we propose three specific aims: Objective 1. Determine the functional role of Ron/TGF2 axis in the development and progression of PDAC. Objective 2. Determine the mechanism(s) that causes aberrant up regulation of Ron in PDAC and whether Ron is differentially expressed in an invasive but non cancer stem cell population. Objective 3. Determine whether targeting the Ron/TGFb axis improves therapy of PDAC. The studies proposed in the current application will investigate the role that interaction of TGF2 and RON kinase play in the invasive properties of PDAC with the premise that this knowledge will contribute to new approaches for therapy. The proposed studies will be conducted as part of the clinical trials and translational research program at the Audie Murphy VA-Hospital for which the PI, Dr. James Freeman, directs the molecular oncology group. The goal of this pre-clinical study is to provide the bases for clinical trials in the VA population with the aim of improving survival of VA patients that present with PDAC. A further impact that this award will have on veterans health care is that this research project is integrated with the medical oncology fellowship program and therefore offers an excellent training venue for candidates seeking to become physician-scientist in the VA system. PUBLIC HEALTH RELEVANCE: Pancreatic cancer (PDAC) is the fourth leading cause of cancer deaths in the VA patient population with a median survival rate of less than 5%. PDAC are highly resistant to chemo- and radiation therapy. Present therapy includes inhibiting aberrantly expressed enzymes and pathways that play a role in tumor progression. However, gaps exist between known genetic alterations that give rise to PDAC with how these alterations impact critical signaling pathways that mediate invasiveness and resistance to therapy. We recently found that the interaction of Ron kinase and TGF2 play an important role in the progression of PDAC. Studies proposed in the current application will investigate the mechanisms by which Ron Kinase and TGF2 promote the invasion of PDAC. The knowledge gained from these studies will hopefully contribute to new approaches for therapy.